Significance: Hydrogen sulfide (H₂S) at the right concentration is associated with numerous health benefits in experimental organisms, ranging from protection from ischemia/reperfusion injury to life span extension. Given the considerable translation potential, two major strategies have emerged: supplementation of exogenous H₂S and modulation of endogenous H₂S metabolism.

Recent Advances: Recently, it was reported that hepatic H₂S production capacity is increased in two of the best-characterized mammalian models of life span extension, dietary restriction, and hypopituitary dwarfism, leading to new insights into dietary and hormonal regulation of endogenous H₂S production together with broader changes in sulfur amino acid (SAA) metabolism with implications for DNA methylation and redox status.

Critical Issues: Here, we discuss the role of dietary SAAs and growth hormone (GH)/thyroid hormone (TH) signaling in regulation of endogenous H₂S production largely via repression of H₂S generating enzymes cystathionine γ-lyase (CGL) and cystathionine β-synthase (CBS) on the level of gene transcription, as well as reciprocal regulation of GH and TH signaling by H₂S itself. We also discuss plasticity of CGL and CBS gene expression in response to environmental stimuli and the potential of the microbiome to impact overall H₂S levels.

Future Directions: The relative contribution of increased H₂S to health span or lifespan benefits in models of extended longevity remains to be determined, as does the mechanism by which such benefits occur. Nonetheless, our ability to control H₂S levels using exogenous H₂S donors or by modifying the endogenous H₂S production/consumption equilibrium has the potential to improve health and increase “shelf-life” across evolutionary boundaries, including our own. Antioxid. Redox Signal. 28, 1483–1502.